{
  "abstract": "The hippocampus forms memories of our experiences by registering processed sensory information in coactive populations of excitatory principal cells or ensembles. Fast-spiking parvalbumin-expressing inhibitory neurons (PV INs) in the dentate gyrus (DG)-CA3/CA2 circuit contribute to memory encoding by exerting precise temporal control of excitatory principal cell activity through mossy fiber-dependent feed-forward inhibition. PV INs respond to input-specific information by coordinating changes in their intrinsic excitability, input-output synaptic-connectivity, synaptic-physiology and synaptic-plasticity, referred to here as experience-dependent PV IN plasticity, to influence hippocampal functions. PV IN impairments in early life, when neural circuitry is highly sensitive to experience-dependent refinement, are thought to result in imbalanced excitation and inhibition, impaired cognition, network hyperexcitability and seizures: hallmarks of neurodevelopmental disorders (NDDs) such as Autism Spectrum Disorder and epilepsy. Discovery of transcriptional regulators of experience-dependent PV IN plasticity in the adult hippocampus may permit reversal of these developmental impairments. Here, in a screen designed to capture the PV IN intrinsic program induced by increased mossy fiber inputs, a trigger for experience-dependent PV IN plasticity, we identify the homeobox gene Meis2 as a regulator of experience-dependent PV IN plasticity gene (XPG) in the adult DG-CA3/CA2 circuit. We found that a significant number of upregulated XPGs also exhibit haploinsufficiency in ASDs, epilepsies, and schizophrenia. We demonstrate that virally-mediated rescue of experience-dependent Meis2 upregulation in CA3/CA2 PV INs in a NDD risk mouse model in adulthood is sufficient to restore experience-dependent PV IN plasticity, spatial and social memory, ensemble specificity, suppression of network hyperexcitability and seizures. Together, these findings suggest that experience-dependent PV IN plasticity is a convergent mechanism for NDD risk genes that can be re-instated in adulthood to reverse developmental deficits in circuitry, network excitability and cognition.",
  "abstract_shown": true,
  "affiliations": [
    "BROAD Institute of MIT and Harvard, Cambridge, MA, USA",
    "Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, USA",
    "Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA",
    "Harvard Stem Cell Institute, Cambridge, MA, USA",
    "Department of Neuroscience, Tufts University School of Medicine, Boston, MA, USA",
    "Department of Molecular Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA",
    "Department of Brain Sciences, Daegu Gyeongbuk Institute of Science and Technology, Daegu, South Korea",
    "Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA",
    "Department of Psychology, University of Michigan, Ann Arbor, MI, USA",
    "Neuroscience Graduate Program, University of Michigan, Ann Arbor, MI, USA",
    "BROAD Institute of MIT and Harvard, Cambridge, MA, USA. asahay@mgh.harvard.edu",
    "Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, USA. asahay@mgh.harvard.edu",
    "Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. asahay@mgh.harvard.edu",
    "Harvard Stem Cell Institute, Cambridge, MA, USA. asahay@mgh.harvard.edu"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 14,
  "authors": [
    {
      "affs": [
        0,
        1,
        2,
        3
      ],
      "name": "Yu‐Tzu Shih",
      "orcid": "0000-0001-8266-8087"
    },
    {
      "affs": [
        0,
        1,
        2,
        3
      ],
      "name": "Jason Bondoc Alipio",
      "orcid": "0000-0001-9315-345X"
    },
    {
      "affs": [
        4
      ],
      "name": "Zin‐Juan Klaft",
      "orcid": "0000-0002-8208-7263"
    },
    {
      "affs": [
        0,
        1,
        2,
        3
      ],
      "name": "Nathaniel Green"
    },
    {
      "affs": [
        0,
        1,
        2,
        3
      ],
      "name": "Alok Nath Mohapatra",
      "orcid": "0000-0002-9994-6407"
    },
    {
      "affs": [
        0,
        1,
        2,
        3
      ],
      "name": "Travis D. Goode",
      "orcid": "0000-0003-1432-8894"
    },
    {
      "affs": [
        0,
        1,
        2,
        3
      ],
      "name": "Muthu Panchanatham"
    },
    {
      "affs": [
        1,
        2,
        3
      ],
      "name": "Devesh Pathak"
    },
    {
      "affs": [
        5
      ],
      "name": "Lai Ping Wong",
      "orcid": "0000-0003-1025-8833"
    },
    {
      "affs": [
        5
      ],
      "name": "Ruslan I. Sadreyev",
      "orcid": "0000-0002-4240-5466"
    },
    {
      "affs": [
        6
      ],
      "name": "Jung Ho Hyun",
      "orcid": "0000-0003-0185-5943"
    },
    {
      "affs": [
        7,
        8,
        9
      ],
      "name": "Omar J. Ahmed",
      "orcid": "0000-0003-3300-7658"
    },
    {
      "affs": [
        4
      ],
      "name": "Chris G. Dulla",
      "orcid": "0000-0002-6560-6535"
    },
    {
      "affs": [
        10,
        11,
        12,
        13
      ],
      "name": "Amar Sahay",
      "orcid": "0000-0003-0677-1693"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/60w6y94m27fe6.bib",
  "cited_by": 7,
  "doi": "10.1038/s41586-026-10907-8",
  "fulltext_url": null,
  "id": "60w6y94m27fe6",
  "issns": [
    "0028-0836",
    "1476-4687"
  ],
  "landing_url": "https://doi.org/10.1038/s41586-026-10907-8",
  "language": "en",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "2804|Neuroscience and Neuropharmacology Research"
    ]
  ],
  "openalex": "W7202253421",
  "pdf_url": null,
  "pmcid": "PMC11774442",
  "pmid": "39877097",
  "published": "2026-08-12",
  "publisher": "Nature Portfolio",
  "ris": "https://research.draconitic.com/paper/60w6y94m27fe6.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T13:26:53Z",
      "native_id": "W7202253421",
      "source": "openalex",
      "url": "https://doi.org/10.1038/s41586-026-10907-8"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "openalex:2804|Neuroscience and Neuropharmacology Research",
      "subfield": "neuroscience"
    }
  ],
  "title": "Procognitive restoration of PV neuron plasticity in neurodevelopmental disorders",
  "title_text": "Procognitive restoration of PV neuron plasticity in neurodevelopmental disorders",
  "type": "peer-reviewed",
  "updated_at": "2026-11-08T13:20:49Z",
  "url": "https://research.draconitic.com/paper/60w6y94m27fe6",
  "venue": "Nature",
  "versions": []
}